Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy

总结-这个新的R01应用的首要目标是研究线粒体的失调， 负责维持正常代谢的网络是癌症的既定标志。这种破坏 细胞代谢，导致活性氧（ROS）的异常积累，引发 适应不良信号传导是一种新兴的导致电离辐射（IR）抵抗（IRR）的新机制 以及恩杂鲁胺（ENZ）抗性（ENZR）。在这方面，最近确定了一个线粒体信号 轴以锰超氧化物歧化酶（MnSOD）为中心，当赖氨酸的乙酰化（Ac）状态 68（K68-Ac）被改变，破坏细胞代谢，导致异常的ROS水平（Zhu，Nature Commun.， 2019年）。此外，表达MnSOD K68-Ac模拟突变体（MnSODK68 Q）的LNCaP细胞表现出IRR/ENZR， 增加的HIF 2a，已知促进干细胞特性，以及两个干细胞标志物Oct4和SOX 2。因此，在本发明中， 我们试图证明MnSOD-K68-Ac可以通过改变MnSOD的结构组成来驱动IRR和/或ENZR 和酶活性，以及在更广泛的背景下，通过细胞干细胞样机制的肿瘤生长和存活。 最后，暴露于GC4419（一种类似MnSOD的化学试剂）是否会逆转IRR/ENZR 表型？因此，假设暴露于IRR和/或ENZR的前列腺肿瘤细胞增加MnSOD-1。 K68-Ac，在细胞和线粒体水平上破坏正常的MnSOD生物学（即，异常ROS）， 通过增加HIF 2a启动细胞重编程，导致谱系可塑性，这是肿瘤细胞的一种变化， 细胞命运和IRR和/或ENZR肿瘤表型。MnSOD-K_（68）-Ac是一种新的催化剂， IRR和IRR/ENZR肿瘤的新治疗干预。最后，使用GC 4419，其化学性质 替代MnSOD活性，我们问是否超氧化物解毒逆转/转换这些IRR/ENZR前列腺 通过恢复正常代谢将肿瘤细胞转化为敏感表型

SUMMARY - The overarching goal of this new R01 application is to investigate the dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer. This disruption of cellular metabolism, leads to the aberrant accumulation of reactive oxygen species (ROS), triggering maladaptive signaling that is an emerging, novel mechanism leading to ionizing radiation (IR) resistance (IRR) as well as enzalutamide (ENZ) resistance (ENZR). In this regard, recently identified a mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD) which, when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cellular metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, LNCaP cells expressing a MnSOD K68-Ac mimic mutant (MnSODK68Q) exhibited IRR/ENZR, increased HIF2a, known to promote stemness properties, and two stem cell markers, Oct4 and SOX2. As such, we seek to show that MnSOD-K68-Ac may drive IRR and/or ENZR, by altering MnSOD’s structural composition and enzymatic activity, and in a broader context, tumor growth and survival via a cell stemness-like mechanism. Finally, will GC4419 exposure, a chemical agent that acts as a MnSOD mimic, reverse the IRR/ENZR phenotype? Thus, it is hypothesized that prostate tumor cells exposed to IRR and/or ENZR increase MnSOD- K68-Ac, disrupting normal MnSOD biology at the cellular and mitochondrial level (i.e., aberrant ROS), which initiates cellular reprogramming, via increased HIF2a, leading to lineage plasticity properties, a change in tumor cell fate, and an IRR and/or ENZR tumor phenotype. It is also proposed that MnSOD-K68-Ac is a novel axis for new therapeutic interventions in IRR and IRR/ENZR tumors. Finally, using GC4419, which that chemically replaces MnSOD activity, we ask whether superoxide detoxification reverts/converts these IRR/ENZR prostate tumor cells to a sensitive phenotype by restoring normal metabolism